Oxophenyl-cyclohexyl-propanolamine derivatives, production and use therof in therapeutics

ABSTRACT

The invention relates to the compounds of general formula (I)  
                 
 
where R 1  represents H, a (C1-C4)alkyl, —CO(C1-C4)alkyl, (C1-C4)alkylphenyl or —CO-phenyl group, said phenyl being optionally substituted, R 2  represents H, a halogen atom, an —S(O) z R 3 , —NHSO 2 R 3 , —NHSO 2 -phenyl or —NHSO 2 —(C1-C4)alkylphenyl group where z is equal to 0, 1 or 2 and where R 3  represents a (C1-C4)alkyl group, said phenyl being optionally substituted; 
 
A is chosen from  
                 
 
where n is equal to 0, 1 or 2, R 4  and R 5  represent H, a (C1-C4)alkyl, hydroxyl, cyano, phenyl, benzyl, piperidyl, —CONH 2 , —CO-phenyl, —COOR 3 , —CH(phenyl) (OH) and —C(phenyl) 2 (OH) group, or R 4  and R 5  form together an optionally substituted 6-membered aromatic ring, R 6  represents H, a (C1-C4)alkyl, phenyl or benzyl group, and B represents a 5- or 6-membered nitrogen-containing heterocycle or homocycle optionally fused with a phenyl group or optionally substituted; their addition salts; their method of preparation and their therapeutic application.

The present invention relates to oxophenylcyclohexylpropanolaminederivatives, their preparation and their therapeutic application.

The present invention relates to compounds corresponding to formula (I):

in which:

-   -   R₁ represents a hydrogen atom or a (C1-C4)alkyl group, a        —CO(C1-C4)alkyl group, a (C1-C4)alkylphenyl group or a        —CO-phenyl group, said phenyl being optionally substituted with        one to three groups chosen independently of each other from        halogen atoms, (C1-C4)alkyl and (C1-C4)alkoxy groups;    -   R₂ is chosen from one of the following groups:        -   a hydrogen atom,        -   a halogen atom,        -   an —S(O)_(z)R₃ group,        -   an —NHSO₂R₃ group,        -   an —NHSO₂-phenyl group, or        -   an —NHSO₂—(C1-C4)alkylphenyl group,    -   where z is equal to 0, 1 or 2 and where R₃ represents a        (C1-C4)alkyl group, said phenyl being optionally substituted        with one to three groups chosen independently from each other        from halogen atoms, (C1-C4)alkyl and (C1-C4)alkoxy groups; and    -   A is chosen from one of the groups of formula:        in which:    -   n is equal to 0, 1 or 2,    -   R₄ and R₅ are carried either by different carbon atoms, or by        the same carbon atom of the ring to which they are attached, and        are chosen independently of each other from the following        groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano,        phenyl, benzyl, piperidyl, —CONH₂, —CO-phenyl, —COOR₃ (where R₃        is as defined above), —CH(phenyl)(OH) and —C(phenyl)₂(OH) group,        at least one of R₄ or R₅ being different from a hydrogen atom,    -   or R₄ and R₅ are carried by adjacent carbon atoms of the ring to        which they are attached and form together with the carbon atoms        carrying them a 6-membered aromatic ring optionally substituted        with 1 to 3 (C1-C4)alkyl or (C1-C4)alkoxy groups,    -   R₆ represents a hydrogen atom or a (C1-C4)alkyl, phenyl or        benzyl group, and    -   B represents a saturated or unsaturated, 5- or 6-membered        cycloalkyl group optionally containing 1 or 2 nitrogen atoms,        this cycloalkyl group being itself condensed with a phenyl group        or substituted with one to three groups chosen from phenyl and        carbonyl groups.

The compounds of formula (I) may contain one or more asymmetric carbonatoms. Moreover, the cyclohexyl group of these compounds has a geometricasymmetry. The signs * in formula (I) above denote carbons which cangive rise to different geometric configurations.

The compounds of formula (I) can therefore exist in the form ofenantiomers or diastereoisomers. These enantiomers, diastereoisomers,and mixtures thereof, including the racemic mixtures, form part of theinvention.

Preference is given in particular to the compounds of formula (I)according to the invention which have the following configuration:

The compounds of formula (I) can exist in the form of bases or ofaddition salts with acids. Such addition salts form part of theinvention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids useful for example for thepurification or isolation of the compounds of formula (I) also form partof the invention.

The compounds of formula (I) can also exist in the form of hydrates orsolvates, namely in the form of associations or combinations with one ormore molecules of water or with a solvent. Such hydrates and solvatesalso form part of the invention.

In the context of the present invention, there is understood to mean by:

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   a (C1-C4)alkyl group: a linear or branched saturated aliphatic        group comprising from 1 to 4 carbon atoms (it being of course        understood that such a group can only be linear when it        comprises less than 3 carbon atoms, and that such a group may be        linear or branched when it comprises 3 or 4 carbon atoms). By        way of examples, there may be mentioned methyl, ethyl, propyl,        isopropyl, butyl and isobutyl groups, and the like;    -   a (C1-C4)alkoxy group: an —O—(C1-C4)alkyl radical where the        (C1-C4)alkyl group is as defined above; and    -   a (C1-C4)alkylphenyl group: a group of formula —(CH₂)_(x)-phenyl        where x is between 1 and 4.

Among the compounds of formula (I) which are the subject of theinvention, there may be mentioned the preferred compounds in which:

-   -   R₁ represents a hydrogen atom;    -   and/or R₂ represents an —SO₂R₃ or —NHSO₂R₃ group where R₃ is as        defined above (R₃ advantageously representing a methyl group or        butyl group);    -   and/or A is chosen from one of the groups of formula:    -   in which n is equal to 0 or 1, R₄, R₅, R₆ and B being as defined        above.

Among the compounds of formula (I) which are the subject of theinvention, other preferred compounds are those in which:

-   -   R₁ represents a hydrogen atom;    -   R₂ represents an —SO₂R₃ or —NHSO₂R₃ group, where R₃ is as        defined above (R₃ advantageously representing a methyl group);        and    -   A is chosen from one of the following groups:        -   a group of formula    -   in which n is equal to 0 or 1 and R₄ and R₅ are carried either        by different carbon atoms, or by the same carbon atom of the        ring to which they are attached and are chosen independently of        each other from the following groups: a hydrogen atom, a        (C1-C4)alkyl, hydroxyl, cyano, phenyl, benzyl, piperidyl,        —CONH₂, —CO-phenyl, —COOR₃ (where R₃ is as defined above),        —CH(phenyl) (OH) and —C(phenyl)₂(OH) group, at least one of R₄        or R₅ being different from a hydrogen atom,        -   a group of formula    -   in which n is equal to 0 or 1 and the aromatic ring is        optionally substituted with 1 to 3 groups chosen independently        of each other from (C1-C4)alkyl and (C1-C4)alkoxy groups,        -   a group of formula    -   in which n is equal to 0 or 1 and R₆ represents a hydrogen atom        or a benzyl group, and        -   a group of formula    -   in which n is equal to 0 or 1 and B represents a saturated or        unsaturated 5- or 6-membered cycloalkyl group optionally        containing 1 or 2 nitrogen atoms, this cycloalkyl group being        itself fused with a phenyl group or substituted with one to        three groups chosen from phenyl and carbonyl groups.

In the text which follows, the expression protecting group Pg isunderstood to mean a group which makes it possible, on the one hand, toprotect a reactive functional group such as a hydroxyl or an amineduring synthesis and, on the other hand, to regenerate the intactreactive functional group at the end of synthesis. Examples ofprotecting groups and methods of protection and of deprotection aregiven in “Protective groups in Organic Synthesis”, Green et al., 2^(nd)Edition (John Wiley & Sons, Inc., New York).

In accordance with the invention, the compounds of general formula (I)may be prepared according to the method described in scheme 1.

According to scheme 1, the ketone functional group of the compound offormula (II) is converted in step (i) to an amine group according tomethods well known to a person skilled in the art (for example byreductive amination). The amine (III) is partially protected with theaid of a protecting group Pg, such as an optionally substituted benzylgroup (for example a para-methoxybenzyl group) or a methoxyethoxymethyl(MEM) group. It is preferable to use here protecting groups which onlypartially protect the reactivity of the amine functional group, that isto say which do not adversely affect its nucleophilic character.However, in the case where R₂ represents an SOR₃ group where R₃ is a(C1-C4)alkyl group, a compound (III) carrying a primary amine (Pg=H inscheme 1) will be preferably used as starting material.

In step (ii), the compound of formula (III) obtained at the end of step(i) is reacted with the epoxide of formula (IV), in which R₁ and R₂ areas defined above. The compounds of formula (IV) are known in theliterature (for example in the patent application published under thenumber WO 02/44139) or may be prepared by methods similar to the methodsdescribed therein. In the case where R₂ can react during this step (ii)or subsequent steps, it is protected beforehand by means of protectinggroups well known to persons skilled in the art.

During step (ii), in the case where the primary amine is partiallyprotected in the compound (III), the compound (III) can only react witha single molecule of the epoxide (IV), and not with two molecules, thusavoiding the formation of reactive by-products.

Step (ii) leads to the amino alcohol of formula (V). This step is forexample carried out in an organic solvent, such as a lower alcohol suchas methanol, ethanol, isopropanol or tert-butanol, or in dimethylsulfoxide, in a linear or cyclic ether, in an amide such asdimethylformamide or dimethylacetamide, or in a mixture of thesesolvents, preferably using at least equimolar quantities of thereagents. The reaction temperature is advantageously between roomtemperature and the reflux temperature of the chosen solvent.

When R₁ represents a hydrogen atom, it is preferable to protect thehydroxyl functional group with a protecting group in order to increasethe yield of the reaction. To this effect, it is possible to use thecustomary protecting groups for phenol groups, such asmethoxyethoxymethyl (MEM), trimethylsilylethoxymethyl (SEM), optionallysubstituted benzyl, or benzoyl.

In the case where R₂ represents an SOR₃ group where R₃ is a (C1-C4)alkylgroup, the nitrogen of the compound (V) will be further protected withan amino-protecting group, such as t-butyloxycarbonyl (BOC) (Pg=BOC inscheme 1 for the compounds (V), (VI) and (VII)), according to methodsknown to persons skilled in the art.

In step (iii), the ethyl ester of the compound (V) obtained at the endof step (ii) is hydrolyzed to an acid (VI) by treating with a base, forexample sodium hydroxide in a solvent or a mixture of solvents, such asan ethanol/water mixture.

The amide of formula (VII) is obtained in step (iv) by reacting the acid(VI) with an amine of formula:

-   -   in which A is defined in relation to formula (I) described        above, in the presence of a coupling agent, for example        1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),        benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate (BOP) or        benzotriazol-1-yloxy-N,N′-tetramethyluronium tetrafluoroborate        (TBTU), and in the presence of a base such as triethylamine or        pyridine, in a solvent such as dichloromethane, acetonitrile or        chloroform. It is also possible to activate the acid functional        group of the compound (VI) in the form of an acid chloride or a        carbonic anhydride, according to techniques known to persons        skilled in the art.

The compounds of formula (I) are finally obtained, in step (v) afterremoving the protecting groups by means of techniques known to personsskilled in the art. In particular, when the protecting groups are benzylgroups, the deprotection is carried out by means of hydrogen in thepresence of palladium on carbon, in a solvent such as ethanol. In scheme1, it is of course understood that it is possible to use, as startingmaterial (II), an ester other than an ethyl ester, for example a methylor propyl ester or any other lower alkyl ester.

The preparation of the compounds of formula (II), which are useful forcarrying out the method presented in scheme 1 above, may be carried outaccording to the method presented in scheme 2, illustrated by way ofexample for the preparation of an ethyl ester as compound (II).

According to scheme 2, the compound of formula (VIII) is condensed, instep (vi), with the compound of formula (IX), in which Hal represents ahalogen atom, preferably bromine, for example according to the methoddescribed by MEYERS et al., in J. Org. Chem., 1974, 39, 2787. Theintermediate alcohol of formula (X) thus obtained is converted, in step(vii), to an unsaturated compound (XI), for example with the aid ofSOCl₂ in pyridine according to the method described by GONZALES-CAMENOet al., in Tetrahedron, 1994, 50, 10971 or with the aid of POCl₃, asdescribed for example in Org. Prep. Proced. Int., 1995, 27, 122.

The unsaturated compound (XI) is then reduced, in step (viii), to acompound (XII) according to conventional methods, for example with theaid of hydrogen in the presence of palladium on carbon, in a solventsuch as ethanol.

The hydrolysis of the acetal group of the compound (XII) is carried out,in step (ix), in a similar manner to the reaction described by SZANTAYet al. in Tetrahedron, 1996, 52(33), 11053, namely with the aid ofhydrochloric acid in acetone, and leads to compound (XIII), which isthen hydrolyzed to compound (II), in step (x), according to the methoddescribed by SEEBACH et al. in Synthesis Communications, 1982, 138 or byNELSON et al. in J. Org. Chem., 1994, 59(9), 2577. Alternatively,compound (XII) may be directly converted to compound (II) by heatingunder reflux in ethanol or by adding sulfuric acid, according to themethod described by DEGRAW et al. in J. Med. Chem., 1992, 35(2), 320 orby TAYLOR et al. in Heterocycles, 1996, 43(2), 323.

It is of course understood that a method identical to that presented inscheme 2 could be carried out for the preparation of compounds (II) inthe form of esters other than ethyl ester, by hydrolyzing compound (XII)with the aid of alcohols carrying alkyl groups different from an ethylgroup.

In schemes 1 and 2, the starting compounds and the reagents, when theirmode of preparation is not expressly described, are commerciallyavailable or are described in the literature, or may be preparedaccording to methods which are described therein or which are known topersons skilled in the art.

The following examples describe the preparation of certain compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The numbers for the compoundsexemplified refer to those given in the table below, which illustratesthe chemical structures and the physical properties of some compoundsaccording to the invention.

Preparation 1:trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid

(Intermediate product of formula (VI) where R₁=Pg=benzyl andR₂═—NH—SO₂—CH₃)

1.1: ethyl trans-4-[4-(benzylamino)cyclohexyl]-benzoate

A solution of 8.51 ml of benzylamine (77.95 mmol) and of 16 g of ethyl4-(cyclohexanone)-benzoate (64.96 mmol) in trimethyl orthoformate (192ml) is heated for 18 h at 50° C. The solvents are evaporated underreduced pressure and 267 ml of ethanol are added, followed by 2.457 g ofsodium borohydride. The reaction mixture is kept stirring for 2 h. Thesolvents are evaporated under reduced pressure and dichloromethane andwater are added. The aqueous phase is extracted three times withdichloromethane. The organic phases are dried over magnesium sulfate andconcentrated under reduced pressure. Ethyltrans-4-[4-(benzylamino)cyclohexyl]benzoate is obtained in the form ofan oil (14.69 g, 67%) after purification on silica gel (eluent: ethylacetate/ethanol 90/10). [M+H⁺]=282.2

1.2: ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate

A mixture of 818 mg (1.82 mmol) of4-benzyloxy-3-(N-tert-butoxycarbonyl-N-methylsulfonylamino)-1-((2S)-2,3-epoxypropoxy)benzeneand 450 mg (1.82 mmol) of ethyltrans-4-[4-(benzylamino)cyclohexyl]benzoate in the form of a base isheated under reflux in 15 ml of absolute ethanol for 16 hours. Themixture is cooled, 3 ml of an ethanol solution saturated withhydrochloric acid are added thereto and the medium is heated at 50° C.for 6 hours. The solvent is evaporated and the medium is taken up in amixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml ofethyl acetate. The organic phase is washed with a saturated aqueous NaClsolution. The organic phase is dried, filtered and the solvent isevaporated under reduced pressure. The crude product is purified bychromatography on a silica gel column, eluting with a methylenechloride/methanol/NH₄OH (95/5/0.5) mixture. The title compound isobtained in the form of a white solid. [M+H⁺]=687.

1.3:trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy]-2-hydroxypropyl}amino)-cyclohexyl]benzoicacid

A mixture of 4.48 g (5.71 mmol) of ethyl4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoateand 38 ml of a 1N aqueous sodium hydroxide solution in 114 ml of ethanolis heated at 50° C. overnight. The solvents are evaporated, the mediumis taken up in water and a 1N hydrochloric acid solution is gently addedto pH=1. The medium is filtered and dried under vacuum. The titlecompound (4.05 g, 94%) is thus obtained in the form of a white solid(melting point=160° C.).

Preparation 2:trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid

(Intermediate product of formula (IV) where R₁=Pg=benzyl andR₂═—SO₂—CH₃)

2.1: ethyltrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl)amino)cyclohexyl]benzoate

This product is obtained by carrying out the procedure as described inPreparation 1.2 above, using ethyl 4-[4-(benzylamino)cyclohexyl]benzoateand 4-benzyloxy-3-methylsulfonyl-1-((2S)-2,3-epoxypropoxy)benzene,described in patent application WO 99/65895, and without adding theretothe hydrochloric acid solution in ethanol. [M+H⁺]=672.

2.2:trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid

The procedure is carried out in a manner similar to Preparation 1.3above, but using ethyl4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoate.8.13 g (93%) of the title compound are thus obtained in the form of awhite solid (melting point=128-130° C.).

EXAMPLE 1trans-N-[5-({(2S)-3-[(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]methanesulfonamide(compound No. 4) 1.1:N-[5-({(2S)-3-[benzyl(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-(benzyloxy)phenyl]methane-sulfonamide

A solution of 2 g (2.88 mmol) oftrans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoicacid (Preparation 1), 0.78 g (5.76 mmol) of 1-hydroxybenzotriazole, 1.1g (5.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1.2 mlof triethylamine and 1.01 ml (5.76 mmol) of 4-benzylpiperidine in amixture of 26 ml of dichloromethane and 5 ml of acetonitrile is stirredfor 24 hours. The solvents are evaporated under reduced pressure.Dichloromethane and water are added and the organic phase is washedthree times with water. The organic phases are dried over magnesiumsulfate and concentrated under reduced pressure.N-[5-({(2S)-3-[benzyl(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-(benzyloxy)phenyl]methanesulfonamideis obtained in the form of a white solid (1.355 g, 57%) afterpurification on silica gel (eluent: dichloromethane/methanol 90/10).[M+H⁺]=816.6.

1.2:trans-N-[5-({(2S)-3-[(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl)cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]methanesulfonamide

A suspension of 1.35 g (1.65 mmol) ofN-[5-({(2S)-3-[benzyl(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}cyclohexyl)amino]-2-hydroxy-propyl}oxy-2-(benzyloxy)phenyl]methanesulfonamideand of 0.77 g of palladium on carbon (10% Pd, 50% in water) in 130 ml ofethanol is placed under a hydrogen atmosphere and with stirring for 2hours. The catalyst is then filtered and the solvents are evaporatedunder reduced pressure. The title compound is obtained in the form of awhite solid (0.53 g) after purification on silica gel (eluent: gradient,dichloromethane/methanol/aqueous ammonia, 99/1/0.1 to 85/15/1.5).

Yield=50%; melting point=100-110° C.; [M+H⁺]=636.6; ¹H NMR (CDCl₃+D₂O,300 MHz) : 1.1-2.05 (m, 14H), 2.02-2.18 (m, 3H), 2.45-2.7 (m, 5H),2.7-2.9 (m, 2H), 2.95 (s, 3H), 3.7-3.95 (m, 3H), 4-4.1 (m, 1H), 4.6-4.8(bm, 1H), 6.55 (dd, 1H), 7.0-7.3 (m, 9H).

EXAMPLE 2trans-N-[2-hydroxy-5-({(2S)-2-hydroxy-3-[(4-{4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}-cyclohexyl)amino]propyl}oxy)phenyl]methanesulfonamide(compound No. 3)

By carrying out the procedure as described in Example 1, using4-methylpiperidine in step 1.1, the title compound (42 mg) is obtainedin the form of a white solid.

Yield=16%; melting point=90-100° C.; [M+H⁺]=560.4; ¹H NMR (DMSO-D6, 300MHz): 0.8-2.05 (m, 14H), 0.88 (d, 3H), 2.3-3 (m, 5H), 3.1-3.5 (m, 3H),2.90 (s, 3H), 3.7-3.95 (m, 3H), 6.55 (dd, 1H), 6.7-6.82 (m, 3H),7.18-7.32 (m, 4H).

EXAMPLE 3trans-4-{[(2S)-2-hydroxy-3-({4-[4-({4-[hydroxy(phenyl)methyl]piperidin-1-yl}carbonyl)phenyl]-cyclohexyl}amino)propyl]oxy}-2-(methylsulfonyl)phenol(compound No. 9)

By carrying out the procedure described in Example 1, but usingtrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (Preparation 2) and phenyl(piperidin-4-yl)methanone in step 1.1,the title compound (20 mg) is obtained in the form of a white solid.

Yield=7.5%; melting point=120° C.; [M+H⁺]=637; ¹H NMR (DMSO-D6+D₂O, 500MHz): 1-1.35 (m, 5H), 1.45 (dd, 2H), 1.65-1.85 (m, 4H), 1.95-2.05 (m,2H), 2.45-2.56 (m, 2H), 2.6-2.7 (m, 1H), 2.75-2.8 (m, 1H), 2.82-2.95 (m,1H), 3.19 (s, 3H), 3.45-3.6 (m, 1H), 3.8-3.9 (m, 3H), 4.28 (d, 1H),4.3-4.45 (m, 1H), 6.88 (d, 1H), 7.1 (d, 1H), 7.12-7.2 (m, 10H).

EXAMPLE 4trans-4-{[(2S)-3-({4-[4-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)phenyl]cyclohexyl}amino)-2-hydroxypropyl]oxy}-2-(methylsulfonyl)phenol(compound No. 11)

By carrying out the procedure as described in Example 1, but usingtrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (Preparation 2) and isoindoline in step 1.1, the title compound isobtained (34 mg) in the form of a white solid.

Yield=14%; melting point=110° C.; [M+H⁺]=565; ¹H NMR (DMSO-D6+D₂O, 500MHz): 1.23 (dd, 2H), 1.47 (dd, 2H), 1.82 (bd, 2H), 2 (bs, 2H), 2.49-2.58(m, 1H), 2.6-2.7 (m, 1H), 2.75-2.8 (m, 1H), 3.19 (s, 3H), 3.8-3.95 (m,3H), 4.76 (s, 2H), 4.83 (s, 2H), 6.9 (d, 1H), 7.22 (d, 1H), 7.19 (s,1H), 7.2-7.4 (m, 6H), 7.5 (d, 2H).

EXAMPLE 5trans-4-{[(2S)-3-({4-[4-(1,3-dihydro-1′H-spiro[indene-2,4′-piperidin]-1′-ylcarbonyl)phenyl]-cyclohexyl}amino)-2-hydroxypropyl]oxy}-2-(methylsulfonyl)phenol(compound No. 13)

By carrying out the procedure as described in Example 1, but usingtrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (Preparation 2) and 1,3-dihydrospiro[indene-2,4′-piperidine] instep 1.1, the title compound is obtained (79 mg) in the form of a whitesolid.

Yield=28%; melting point=125° C.; [M+H⁺]=633; ¹H NMR (DMSO-D6+D₂O, 500MHz): 1.17-1.3 (m, 2H), 1.35-1.65 (m, 4H), 1.68-1.85 (m, 4H), 1.9-2.12(m, 4H), 2.48-2.6 (m, 1H), 2.64-2.7 (m, 1H), 2.76-2.8 (m, 1H), 2.81-2.9(m, 2H), 2.91-3.03 (m, 1H), 3.2 (s, 3H), 3.19-3.29 (m, 1H), 3.5-3.65 (m,1H), 3.85-3.91 (m, 2H), 4.35-4.5 (m, 1H), 6.92 (d, 1H), 7.1-7.22 (m,6H), 7.25-7.38 (m, 4H).

EXAMPLE 6trans-4-{[(2S)-3-({4-[4-(2,3-dihydro-1′H-spiro[indene-1,4′-piperidin]-1′-ylcarbonyl)phenyl]-cyclohexyl}amino)-2-hydroxypropyl]oxy}-2-(methylsulfonyl)phenol(compound No. 15)

By carrying out the procedure as described in Example 1, but usingtrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxy-propyl}amino)cyclohexyl]benzoicacid (Preparation 2) and 1′H-spiro[indene-1,4′-piperidine] in step 1.1,the title compound is obtained (68 mg) in the form of a white solid.

Yield=24%; melting point=125° C.; [M+H⁺]=633; ¹H NMR (DMSO-D6+D₂O, 500MHz): 1.17-1.3 (m, 2H), 1.35-1.65 (m, 4H), 1.68-1.85 (m, 4H), 1.9-2.12(m, 4H), 2.48-2.6 (m, 1H), 2.64-2.7 (m, 1H), 2.76-2.8 (m, 1H), 2.81-2.9(m, 2H), 2.91-3.03 (m, 1H), 3.2 (s, 3H), 3.19-3.29 (m, 1H), 3.5-3.65 (m,1H), 3.79-3.85 (m, 1H), 3.85-3.91 (m, 1H), 4.37-4.5 (m, 1H), 6.92 (d,1H), 7.1-7.22 (m, 6H), 7.25-7.38 (m, 4H).

EXAMPLE 7trans-4-{[(2S)-3-({4-[4-(3,4-dihydro-1′H-spiro[naphthalene-1,4′-piperidin]-1′-ylcarbonyl)phenyl]cyclohexyl}amino)-2-hydroxypropyl]-oxy}-2-(methylsulfonyl)phenol(compound No. 17)

By carrying out the procedure as described in Example 1, but usingtrans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoicacid (Preparation 2) and3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] in step 1.1, the titlecompound is obtained (93 mg) in the form of a white solid.

Yield=35%; melting point=125° C.; [M+H⁺]=647; ¹H NMR (DMSO-D6+D₂O, 500MHz): 0.8-2.1 (m, 18H), 2.35-3 (m, 4H), 3.2 (s, 3H), 3.32 (bs, 1H),3.62-3.95 (m, 5H), 4.25-4.5 (m, 1H), 6.9 (d, 1H), 6.9-7.52 (m, 10H).

The table which follows illustrates the chemical structures and thephysical properties of some compounds according to the invention. Inthis table:

-   -   in the “salt” column, “-” represents a compound in free base        form,

Me, Et, Ph and Bn represent methyl, ethyl, phenyl and benzyl groups,respectively. TABLE (I)

Melting point No. R₁ R₂ A Salt (° C.) 1 H —NHSO₂CH₃

pamoate 110-160 2 H —NHSO₂CH₃

pamoate 110-150 3 H —NHSO₂CH₃

—  90-100 4 H —NHSO₂CH₃

— 100-110 5 H —SO₂CH₃

— 108-110 6 H —SO₂CH₃

—  85 7 H —SO₂CH₃

— 110 8 H —SO₂CH₃

— 140 9 H —SO₂CH₃

— 120 10 H —NHSO₂CH₃

— 100 11 H —SO₂CH₃

— 110 12 H —SO₂CH₃

—  75 13 H —SO₂CH₃

— 125 14 H —NHSO₂CH₃

— 140 15 H —SO₂CH₃

— 125 16 H —NHSO₂CH₃

— 125 17 H —SO₂CH₃

— 125 18 H —NHSO₂CH₃

— 135 19 H —SO₂CH₃

— 140 20 H —NHSO₂CH₃

—  97 21 H —SO₂CH₃

— 100 22 H —SO₂CH₃

— 110 23 H —NHSO₂CH₃

— 126 24 H —SO₂CH₃

— 112 25 H —SO₂CH₃

— 135

The compounds according to the invention have been the subject ofpharmacological trials which make it possible to determine their agonistactivity effect against beta-3 receptors.

The agonist activity against beta-3 receptors (indicated by theproduction of cAMP induced by the test compound) was studied with theaid of membrane preparations of SKNMC cells (human neuroblastoma cells)in the presence of selective beta-1 and beta-2 antagonists (CGP20712 andICI118551, both at a concentration of 10⁻⁶M). The activity of thecompounds according to the invention (pKa) is greater than or equal to6.0 (it is in general between 6.0 and 7.6). Their efficacy is greaterthan or equal to 60% and is generally in the range from 60 to 90%.

The activities of the compounds according to the invention toward thebeta-1 and beta-2 receptors were studied on the atrium and on thetrachea, respectively, of guinea pigs. The agonist and antagonistactivities were measured. It was thus found that the compounds accordingto the invention are selective toward the beta-3 receptors: indeed, theyare at least 50 times more active toward the beta-3 receptors thantoward the beta-1 or beta-2 receptors.

The compounds according to the invention may therefore be used for thepreparation of medicaments intended in particular for the treatment ofdiseases in which the beta-3 receptors are involved. More particularly,the compounds according to the invention may be used as medicaments withagonist beta-3 action.

Thus, according to another of its aspects, the subject of the inventionis a medicament which comprises a compound of formula (I), or anaddition salt thereof with a pharmaceutically acceptable acid, or ahydrate or a solvate of the compound of formula (I).

Examples of diseases in which the beta-3 receptors are involved areabundantly described in the literature. The compounds of formula (I),and their pharmaceutically acceptable salts, or hydrates or solvates ofthese compounds, can therefore be indicated for the treatment ofgastrointestinal diseases such as inflammatory bowel diseases, forexample irritable bowel syndrome (IBS) or inflammatory bowel disease(IBD), as modulators of intestinal motility, as lipolytics,anti-obesity, anti-diabetic, anti-glaucomatous and cicatrizing agents,as uterine contraction inhibitors, as tocolytics for preventing ordelaying preterm labor, and for the treatment and/or prophylaxis ofdysmenorrhea. In addition, the compounds of formula (I), and theirpharmaceutically acceptable salts, or hydrates or solvates of thesecompounds, may be used in the treatment of certain diseases of thecentral nervous system, for example as psychotropics or antidepressants,and certain disorders of the urinary tract, such as urinaryincontinence.

The present invention, according to another of its aspects, also relatesto a method for treating the pathologies indicated above which comprisesthe administration, to a patient, of an effective dose of a compoundaccording to the invention, or one of its pharmaceutically acceptablesalts, or a hydrate or solvate of this compound.

The present invention also relates to pharmaceutical compositionscomprising, as active ingredient, at least one compound according to theinvention. These pharmaceutical compositions contain an effective doseof a compound according to the invention, or a pharmaceuticallyacceptable salt, a hydrate or solvate of said compound, and at least onepharmaceutically acceptable excipient.

Said excipients are chosen, according to the pharmaceutical dosage formand the desired mode of administration, from the usual excipients whichare known to persons skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intratracheal, intranasal, transdermal or rectal administration, theactive ingredient of formula (I) above, or its optional salt, solvate orhydrate, may be administered in unit form for administration, as amixture with conventional pharmaceutical excipients, to animals and tohuman beings for the prophylaxis or treatment of the above disorders ordiseases.

The appropriate unit forms for administration comprise the oral formssuch as tablets, soft or hard gelatin capsules, powders, granules andoral solutions or suspensions, the forms for sublingual, oral,intratracheal, intraocular or intranasal administration or foradministration by inhalation, the forms for topical, transdermal,subcutaneous, intramuscular or intravenous administration, the forms forrectal administration and implants. For topical application, thecompounds according to the invention may be used in creams, gels,ointments or lotions.

The dose of active ingredient administered is between 0.01 and 20 mg perkilo of body weight of the mammal to be treated, preferably between 0.1and 10 mg/kg. In humans, the dose may vary from 0.5 mg to 1500 mg perday, for example from 2.5 to 500 mg according to the age of the subjectto be treated, the type of treatment (prophylactic or curative) and theseriousness of the condition. The compounds of formula (I) are generallyadministered in unit dosage form of 0.1 to 500 mg, preferably 0.5 to 100mg of active ingredient, between one and five times per day.

There may be particular cases where higher or lower dosages areappropriate; such dosages do not depart from the scope of the invention.According to the usual practice, the dosage appropriate for each patientis determined by the doctor according to the mode of administration, theweight and the response of said patient.

1. A compound corresponding to formula (I):

in which: R₁ represents a hydrogen atom or a (C1-C4)alkyl group, a—CO(C1-C4)alkyl group, a (C1-C4)alkylphenyl group or a —CO-phenyl group,said phenyl being optionally substituted with one to three groups chosenindependently of each other from halogen atoms, (C1-C4)alkyl and(C1-C4)alkoxy groups; R₂ is chosen from one of the following groups: ahydrogen atom, a halogen atom, an —S(O)_(z)R₃ group, an —NHSO₂R₃ group,an —NHSO₂-phenyl group, or an —NHSO₂-(C1-C4)alkylphenyl group, where zis equal to 0, 1 or 2 and where R₃ represents a (C1-C4)alkyl group, saidphenyl being optionally substituted with one to three groups chosenindependently of each other from halogen atoms, (C1-C4)alkyl and(C1-C4)alkoxy groups; and A is chosen from one of the groups of formula:

in which: n is equal to 0, 1 or 2, R₄ and R₅ are carried either bydifferent carbon atoms, or by the same carbon atom of the ring to whichthey are attached, and are chosen independently of each other from thefollowing groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano,phenyl, benzyl, piperidyl, —CONH₂, —CO-phenyl, —COOR₃ (where R₃ is asdefined above), —CH(phenyl)(OH) and —C(phenyl)₂(OH) group, at least oneof R₄ or R₅ being different from a hydrogen atom, or R₄ and R₅ arecarried by adjacent carbon atoms of the ring to which they are attachedand form together with the carbon atoms carrying them a 6-memberedaromatic ring optionally substituted with 1 to 3 (C1-C4)alkyl or(C1-C4)alkoxy groups, R₆ represents a hydrogen atom or a (C1-C4)alkyl,phenyl or benzyl group, and B represents a saturated or unsaturated, 5-or 6-membered cycloalkyl group optionally containing 1 or 2 nitrogenatoms, this cycloalkyl group being itself condensed with a phenyl groupor substituted with one to three groups chosen from phenyl and carbonylgroups; in the form of bases or addition salts with acids, and in theform of hydrates or solvates.
 2. The compound of formula (I) as claimedin claim 1 wherein R₁ represents a hydrogen atom, in the form of basesor addition salts with acids, and in the form of hydrates or solvates.3. The compound of formula (I) as claimed in claim 1 wherein R₂represents an —SO₂R₃ or —NHSO₂R₃ group, where R₃ is as defined in claim1, in the form of bases or addition salts with acids, and in the form ofhydrates or solvates.
 4. The compound of formula (I) as claimed in claim1 wherein A is chosen from one of the following groups: a group offormula

in which n is equal to 0 or 1 and R₄ and R₅ are carried either bydifferent carbon atoms, or by the same carbon atom of the ring to whichthey are attached and are chosen independently of each other from thefollowing groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano,phenyl, benzyl, piperidyl, —CONH₂, —CO-phenyl, —COOR₃ (where R₃ is asdefined in claim 1), —CH(phenyl)(OH) and —C(phenyl)₂(OH) group, at leastone of R₄ or R₅ being different from a hydrogen atom, a group of formula

in which n is equal to 0 or 1 and the aromatic ring is optionallysubstituted with 1 to 3 groups chosen independently of each other from(C1-C4)alkyl and (C1-C4)alkoxy groups, a group of formula

in which n is equal to 0 or 1 and R₆ represents a hydrogen atom or abenzyl group, and a group of formula

in which n is equal to 0 or 1 and B represents a saturated orunsaturated 5- or 6-membered cycloalkyl group optionally containing 1 or2 nitrogen atoms, this cycloalkyl group being itself fused with a phenylgroup or substituted with one to three groups chosen from phenyl andcarbonyl groups; in the form of bases or addition salts with acids, andin the form of hydrates or solvates.
 5. A method for preparing thecompounds of formula (I) according to claim 1 wherein compound offormula (VI), in which R₁ and R₂ are as defined in any one of claims 1to 3 and Pg represents a protecting group:

is reacted with an amine of formula:

in which A is as defined in claim 1 or 4, in the presence of a couplingagent and a base, and in that the protecting group Pg is removed fromthe product thus obtained.
 6. (canceled)
 7. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt, a hydrate or a solvate of thiscompound, and at least one pharmaceutically acceptable excipient.
 8. Amethod for the treatment of diseases in which the beta-3 receptors areinvolved which comprises administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 1. 9. Amethod according to claim 8 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence. 10.The compound of formula (I) as claimed in claim 2 wherein R₂ representsan —SO₂R₃ or —NHSO₂R₃ group, where R₃ is as defined in claim 1, in theform of bases or addition salts with acids, and in the form of hydratesor solvates.
 11. The compound of formula (I) as claimed in claim 2wherein A is chosen from one of the following groups: a group of formula

in which n is equal to 0 or 1 and R₄ and R₅ are carried either bydifferent carbon atoms, or by the same carbon atom of the ring to whichthey are attached and are chosen independently of each other from thefollowing groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano,phenyl, benzyl, piperidyl, —CONH₂, —CO-phenyl, —COOR₃ (where R₃ is asdefined in claim 1), —CH(phenyl)(OH) and —C(phenyl)₂(OH) group, at leastone of R₄ or R₅ being different from a hydrogen atom, a group of formula

in which n is equal to 0 or 1 and the aromatic ring is optionallysubstituted with 1 to 3 groups chosen independently of each other from(C1-C4)alkyl and (C1-C4)alkoxy groups, a group of formula

in which n is equal to 0 or 1 and R₆ represents a hydrogen atom or abenzyl group, and a group of formula

in which n is equal to 0 or 1 and B represents a saturated orunsaturated 5- or 6-membered cycloalkyl group optionally containing 1 or2 nitrogen atoms, this cycloalkyl group being itself fused with a phenylgroup or substituted with one to three groups chosen from phenyl andcarbonyl groups; in the form of bases or addition salts with acids, andin the form of hydrates or solvates.
 12. The compound of formula (I) asclaimed in claim 3 wherein A is chosen from one of the following groups:a group of formula

in which n is equal to 0 or 1 and R₄ and R₅ are carried either bydifferent carbon atoms, or by the same carbon atom of the ring to whichthey are attached and are chosen independently of each other from thefollowing groups: a hydrogen atom, a (C1-C4)alkyl, hydroxyl, cyano,phenyl, benzyl, piperidyl, —CONH₂, —CO-phenyl, —COOR₃ (where R₃ is asdefined in claim 1), —CH(phenyl)(OH) and —C(phenyl)₂(OH) group, at leastone of R₄ or R₅ being different from a hydrogen atom, a group of formula

in which n is equal to 0 or 1 and the aromatic ring is optionallysubstituted with 1 to 3 groups chosen independently of each other from(C1-C4)alkyl and (C1-C4)alkoxy groups, a group of formula

in which n is equal to 0 or 1 and R₆ represents a hydrogen atom or abenzyl group, and a group of formula

in which n is equal to 0 or 1 and B represents a saturated orunsaturated 5- or 6-membered cycloalkyl group optionally containing 1 or2 nitrogen atoms, this cycloalkyl group being itself fused with a phenylgroup or substituted with one to three groups chosen from phenyl andcarbonyl groups; in the form of bases or addition salts with acids, andin the form of hydrates or solvates.
 13. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 2 or apharmaceutically acceptable salt, a hydrate or a solvate of thiscompound, and at least one pharmaceutically acceptable excipient.
 14. Apharmaceutical composition comprising a compound of formula (I)according to claim 3 or a pharmaceutically acceptable salt, a hydrate ora solvate of this compound, and at least one pharmaceutically acceptableexcipient.
 15. A pharmaceutical composition comprising a compound offormula (I) according to claim 4 or a pharmaceutically acceptable salt,a hydrate or a solvate of this compound, and at least onepharmaceutically acceptable excipient.
 16. A pharmaceutical compositioncomprising a compound of formula (I) according to claim 10 or apharmaceutically acceptable salt, a hydrate or a solvate of thiscompound, and at least one pharmaceutically acceptable excipient.
 17. Apharmaceutical composition comprising a compound of formula (I)according to claim 11 or a pharmaceutically acceptable salt, a hydrateor a solvate of this compound, and at least one pharmaceuticallyacceptable excipient.
 18. A pharmaceutical composition comprising acompound of formula (I) according to claim 12 or a pharmaceuticallyacceptable salt, a hydrate or a solvate of this compound, and at leastone pharmaceutically acceptable excipient.
 19. A method for thetreatment of diseases in which the beta-3 receptors are involved whichcomprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 2. 20. A method forthe treatment of diseases in which the beta-3 receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 3. 21. A method forthe treatment of diseases in which the beta-3 receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 4. 22. A method forthe treatment of diseases in which the beta-3 receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 10. 23. A method forthe treatment of diseases in which the beta-3 receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 11. 24. A method forthe treatment of diseases in which the beta-3 receptors are involvedwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 12. 25. A methodaccording to claim 19 for the treatment of gastrointestinal diseasessuch as inflammatory bowel diseases, for example irritable bowelsyndrome (IBS) or inflammatory bowel disease (IBD), as modulators ofintestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 26. Amethod according to claim 20 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 27. Amethod according to claim 21 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 28. Amethod according to claim 22 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 29. Amethod according to claim 23 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.
 30. Amethod according to claim 24 for the treatment of gastrointestinaldiseases such as inflammatory bowel diseases, for example irritablebowel syndrome (IBS) or inflammatory bowel disease (IBD), as modulatorsof intestinal motility, as lipolytics, anti-obesity, anti-diabetic,anti-glaucomatous and cicatrizing agents, as uterine contractioninhibitors, as tocolytics for preventing or delaying preterm labor, andfor the treatment and/or prophylaxis of dysmenorrhea, as psychotropicsor antidepressants, and for the treatment of urinary incontinence.